The human urinary bladder is essentially a two-layered organ, consisting of a muscular outer wall and a highly specialized epithelium lining the lumen. Differentiated urinary bladder epithelium is characterized by the presence of urothelial plaques on the lumenal surface of urinary bladder superficial or umbrella cells. These plaques are characterized by a highly unusual membrane structure, i.e., the asymmetric unit membrane (AUM), with a lumenal leaflet twice as thick as the cytoplasmic leaflet. The thickening of the lumenal leaflet is due to the presence of particles exhibiting a semi-crystalline organization and made up principally of four transmembrane proteins: uroplakin (UP) Ia (27 kDa); UP Ib (28 kDa); UP II (15 kDa) and UP III (47 kDa). UP III is believed to play a role in the formation of the urothelial glycocalyx and may interact, via its cytoplasmic portion, with the cytoskeleton. Hu et al., 2000. J. Cell Biol. 151(5):961-72.
The developmental origin of the urinary bladder is found in endodermal tissue. The bladder arises from the cloaca, a common chamber from which both the bladder and the lower alimentary canal are derived. As development proceeds, the cloaca is divided into the hind gut and the urogenital sinus. The muscular wall of the bladder is induced from the adjacent mesenchyme by signals from bladder epithelium, although the identity of the signal(s) is unknown.
Amongst men in the U.S., bladder cancer accounts for approximately 2% of all malignant tumors and approximately 7% of all urinary tract malignancies, although women experience approximately one-third the incidence of men. Additionally, race plays a factor, with African-American men experiencing nearly twice the age-adjusted incidence of non-Hispanic white males. The American Cancer Society estimates there will be more than 50,000 new bladder cancer cases in the next year, with an estimated 9,500 deaths. For superficial, low-grade disease, chemotherapy is applied intravesically (directly into the bladder) to concentrate the drug at the tumor site and eliminate any residual tumor mass after resection. Systemic chemotherapy and/or radiation are used on high grade disease, commonly in conjunction with radical cystectomy. However, because about 50% of patients with high-stage, high-grade tumors eventually relapse following cystectomy, surgery is seldom performed to palliate symptoms in these patients.
In addition to race and sex factors, chemical exposures are established risk factors for bladder cancer. Chief amongst chemical exposure risk factors are smoking, but occupational exposures, particularly to arylamines, are also significant risk factors.
A number of investigators have described the use of uroplakin antibodies for analysis of the differentiation state of urothelial cells or for diagnosis of metastatic bladder carcinoma. Yu et al., 1992. Epith. Cell Biol. 1:4-b 12; Moll et al. 1993 Verh. Deutsc. Ges. Path. 77 and Moll et al. 1995. Am. J. Pathol. 147:1383-1397.
In vitro investigations of urothelial cells typically utilize cell lines derived from bladder tumors or primary urothelial cells, although a limited number of normal urothelial tissue-derived cell lines have been reported (Christensen et al., 1984, Anticancer Res. 4:319-38). International Patent Application WO 02/102997 discloses homozygous stem cells derived from non-fertilized post-meiosis I diploid germ cells which can purportedly be differentiated into a variety of cell types. See also, Keay et al., 1996, J. Urol. 156(6):2073-8; and Owens et al., 1976, J. Natl. Cancer Inst. 56(4):843-9.